1. Field of the Invention
This invention relates generally to a radiopharmaceutical method and more particularly concerns the use of complexes of technetium-99m and fructose 6-phosphate or fructose 1,6-diphosphate or salts thereof in a process for externally monitoring the kidneys.
2. Description of the Prior Art
Studies of mammalian kidneys by means of the administration of a radiopharmaceutical agent generally involve external visualization or imaging of the kidneys and/or measurement of the clearance of the radiopharmaceutical agent from plasma through the renal system, measurement of the glomerular filtration rate alone of the agent through the kidneys, or measurement of the total renal function--that is, effective renal plasma flow--as the excretion of the agent by both glomerular filtration and renal tubule secretion. In general, if an intravenously administered radiopharmaceutical agent is excreted at least to a significant extent via the kidneys, the agent can be used to image the kidneys. Moreover, if an intravenously administered radiopharmaceutical agent is excreted solely by the kidneys and is cleared from the plasma in a short half-time, then the agent does not bind to any part of the kidneys and can be used to measure effectively renal plasma clearance and, if the agent is not acted upon by the renal tubules, also the glomerular filtration rate. However, if these same conditions are met except that the agent is acted upon by the renal tubules, then the agent can still be used to image the kidneys but only effective renal plasma clearance can be measured.
A determination of whether or not an intravenously administered radiopharmaceutical agent is excreted solely through the kidneys can be made from the rate of disappearance of an intravenously administered radiopharmaceutical agent from the plasma. The rate of disappearance of an intravenously administered radiopharmaceutical agent from the plasma is related to both its distribution throughout the body and its elimination from the body. An analysis of the clearance, or rate of disappearance, of the radiopharmaceutical agent from the plasma--which can be represented by a plot of the logarithm of the experimentally measured radiopharmaceutical activity in the plasma as the ordinate versus time after administration as the abscissa--can define the number and sizes of the individual compartments of distribution of the radiopharmaceutical agent within the body. Since the clearance of the radiopharmaceutical agent from each compartment to the next is an exponential function, the individual components of the experimentally measured plasma clearance curve can be identified by a process of curve peeling. This process of curve peeling or stripping can be performed manually or by means of computer programs such as CSTRIP and NONLIN. A. J. Stedman and J. G. Wagner, Journal of Pharmaceutical Sciences, Vol. 65, No. 7, July 1976, pp. 1006-1010; C. M. Metzler, G. L. Elfing and A. J. McEwen, Biometrics, Vol. 30, No. 3, Sept. 1974.
The terminal slope of the clearance curve represents the renal component after equilibration in all the compartments, if the kidneys are the only ultimate exit from the first compartment (plasma being part of the first volume). By the process of curve stripping, the other exponential functions can be identified. This is done manually by extrapolating the terminal linear portion back to the ordinate and subtracting this extrapolated line from the original curve to obtain a new set of points. A new curve or straight line most closely approximating these new points is thereby identified, again having a terminal linear portion that defines another slope corresponding to a second compartment of distribution. This process of curve stripping is continued until arriving at a final exponential function, that is, until the points obtained as the difference between a curve and its extrapolated terminal linear portion are most closely approximated by a straight line. The number of exponential functions defines the number of individual compartments or volumes of distribution, and their sum defines the total plasma clearance curve. In the alternative this operation can be performed using a computer with available computer programs.
A two-compartment model predicts that a plot of the logarithm of radiopharmaceutical activity in either compartment (in the case of renal function, (1) in the plasma or whole blood or (2) in the renal system) versus time after administration is represented by the sum of two exponential functions. Fitting the sums of the exponential functions to plots of the logarithm of observed radiopharmaceutical activity in a compartment versus time permits the determination of transfer constants and compartmental values. Deviation of such constants and values, and hence of the measured clearance curves, from corresponding constants, values and clearance curves, respectively, for normally functioning kidneys permits diagnosis of renal ailments. If such a semi-quantitative analysis of the clearance through the kidneys can be made the radiopharmaceutical agent can be used not only to externally image the kidneys but also to assess renal function.
The conventional radiopharmaceutical agent for external imaging of the kidneys and assessment of renal function is a complex of ortho-iodohippurate with the radionuclide iodine-131. The .sup.131 I-o-iodohippurate complex is particularly well suited for this purpose because it is excreted through the kidneys exclusively, not through the liver or through both the liver and the kidneys. Due to its exceptionally high organ specificity, .sup.131 I-o-iodohippurate appears to follow the two-compartment model for organ function assessment radiopharmaceutical agents. After intravenous injection, .sup.131 I-o-iodohippurate is cleared from the blood, concentrated in the urine and excreted into the urinary bladder.
However, .sup.131 I-o-iodohippurate suffers the disadvantage of containing the iodine-131 radionuclide which emits gamma rays having the relatively high energy of 0.364 MeV, thereby imposing a relatively low limit on the maximum permissible administration dosage of .sup.131 I-o-iodohippurate. Further the 8 day half-life of the iodine-131 radionuclide results in an excessive residual radiation dose following administration of millicurie quantities of .sup.131 I-o-iodohippurate and performance of the test. This residual radiation is a disadvantage per se and also necessitates that successive radiopharmaceutical tests be spaced by a sufficient number of days after administration of .sup.131 I-o-iodohippurate to permit the background radiation to decay to a sufficiently low level.
The radionuclide technetium-99m has a shorter half life and emits lower energy gamma rays that iodine-131 and would be preferred in complexes with o-iodohippurate. However, o-iodohippurate does not complex satisfactorily with technetium-99m.
Basmadjian et al., "Chemistry of Technetium Phosphate and Phosphonate Complexes: Applications to radiopharmaceuticals," in Nuclear Medicine: State of the Art and Future from the Proceedings of the 15th International Annual Meeting of the Society of Nuclear Medicine in Gronigen, Netherlands on Sept. 13-16, 1977, published in 1978., a report on organ-specific radiopharmaceuticals, disclose that organic compounds with the following phosphonate structures have been shown to complex technetium when the latter is reduced with stannous ions: R--OPO.sub.3 H.sub.2, R--CH.sub.2 --PO.sub.3 H.sub.2 and R--NH--PO.sub.3 H.sub.2. The article points out that in-vivo biodistribution in rabbits indicates that localization of such complexes is governed by the side chain. Although the phosphate group is needed for the chelation of reduced technetium when it is present in the free ionized form, or esterified with alkyl groups, it does not influence in-vivo biodistribution.
Structure-biodistribution relationships show that when the R-group in the above structures is a CH.sub.3 --, CH.sub.3 CH.sub.2 --, HOOCCH.sub.2 --, NH.sub.2 CH.sub.2 --, etc, uptake of the complex in the bones is evident. However, as the chain length is increased, bone uptake is decreased with non-specific biodistribution evident. Furthermore, when the alkyl radical is anywhere from 2 to 5 carbon atoms in length, or when an aryl radical exists, no matter what other functional groups are present in the molecule, a complex "mainly" excreted by the kidneys is obtained. Basmadjian et al. also disclose that, in the case of organic esters of the orthophosphate moiety, of the structure R--OPO.sub.3 H.sub.2 where R is alkyl or aryl, the technetium complex is "mainly" execreted by the kidneys, with a long half-time in the blood, and assert that this behavior indicates some kind of protein binding. Furthermore, Basmadjian, in an oral presentation entitled "Chemistry and Biodistribution of Technetium Phosphate Complexes," presented at the First Annual Meeting on General Radiopharmaceutical Science sponsored by the Radiopharmaceutical Science Council of the Society of Nuclear Medicine in Atlanta, Ga. on Jan. 22, 1978, disclosed that technetium-labelled complexes of glucose 6-phosphate and of fructose 1,6-diphosphate have been studied as bone-specific radiopharmaceutical agents.
However, the Basmadjian et al. and Basmadjian reports do not disclose the technetium-labelled complexes of organic esters of the orthophosphate moiety are excreted solely by the kidneys, but only disclose that such materials are excreted "mainly" by the kidneys. Moreover, such reports indicate that technetium complexes of organic esters of orthophosphate have a long half-time in the blood which indicates some kind of protein binding. However, such binding would prevent a radiopharmaceutical agent from being used to measure effective renal plasma clearance or glomerular filtration rate.